The aim of this project is to gain insight into the question of how antigen stimulates lymphocytes, and particularly how it happens that under some circumstances the antigen will result in antibody production by the lymphocytes concerned, whereas under other circumstances, i.e. with a different antigen dosage or a different molecular form of the antigen, the end result is not stimulation but actually an inhibition of the cells concerned, the state known as immunological tolerance. In pursuance of the goals of this work, heavy emphasis is placed on the nature and characteristics of surface receptors of lymphocytes. We will aim to define what the differences are between thymus-derived (T) and bone-marrow derived (B) lymphocytes with respect to their surface receptors for antigen. This work will necessitate further delineation of the glycoprotein product of the so-called Ir-genes, which have been claimed to be responsible for the production of a non-immunoglobulin receptor for antigen. It is proposed to develop further work in in-bred "nude" mice. These mice are congenitally free of T lymphocytes, and present opportunities for studying the interaction between B lymphocytes and soluble antigen molecules in a milieu not influenced by T lymphocytes, as it is now well known that interaction between T and B lymphocytes, and macrophages, complicate interpretation of tissue culture experiments in antibody formation. A thread of single cell micro-manipulation technology and micro-radio chemistry, developed in our laboratory over the past fifteen years, will serve as a further link between the various projects making up the present research programme. BIBLIOGRAPHIC REFERENCES: Metcalf, D., Nossal, G.J.V., Warner, N.L., Miller, J.F.A.P., Mandel, T.E., Layton, J.E., and Gutman, G.A. (1975). Growth of B-lymphocyte colonies in vitro. J. Ep. Med. 142:1534-1549. Metcalf, D., Warner, Nossal, G.J.V., Miller, J.F.A.P., Shortman, K., and Rabellino, E. (1975). Growth of B lymphocyte colonies in vitro from mouse lymphoid organs. Nature 255:630-631.